The present invention relates to an aerosol therapy device, wherein an aerosol is generated in an aerosol generating device and is supplied through a nosepiece to a patient's nasal cavities via a single pulsed main aerosol flow.
The four paranasal sinuses (maxillary, sphenoid, frontal and ethmoid) develop as outpouchings of the nasal mucosa. At birth, they are fluid filled and pneumatization occurs gradually during childhood so that by the age of about 16 years all sinuses are generally fully developed. The sinuses remain connected to the nasal cavity via narrow ostia with a lumen diameter of 1 to 3 mm. The ostia of the frontal, maxillary and anterior ethmoid sinuses open to the osteomeatal complex. The osteomeatal complex is important because the frontal, ethmoid and maxillary sinuses all drain through this area. Thus, ostial patency is necessary for adequate ventilation of the sinuses and the penetration of an aerosol through the ostia to result in aerosol deposition within the paranasal sinuses.
Studies using various models of the human nose have demonstrated that when current aerosol therapy devices are used for sinunasal therapy, aerosol deposition in the paranasal sinuses is less than expected and desired. One contributing factor to the difficulties of current nebulized sinunasal therapies in achieving adequate aerosol deposition is the anatomical features of the paranasal sinuses. As described supra, the opening size of the ostia, which is very small, also has a great influence on aerosol deposition.
Due to its anatomical structure, it is thought that the sinus cavity behaves like a kind of Helmholtz resonator, which is a container of gas with an open hole at the end of a neck. Such a container has a specific resonance frequency wherein the air within the neck (airplug) will be most easily moved. An outside variation in air pressure causes the air plug in the neck (i.e., the ostia of the sinuses) to oscillate in and out. Thus, by oscillating the ostia at the appropriate frequency, one is able to increase gas exchange via the ostia.
As shown in “Eindringvermogen von Aerosolen in Nebenraume”, H. Kauff, Archiv. Klin. Exper. Ohren-, Nasen- and Kehlkopfheilk. 190, 95-108 (1968), the use of pressure oscillations and co-vibrations can cause aerosols to penetrate the paranasal sinuses, through which the main aerosol flow through the nasal cavities does not otherwise actively flow. An example of these effect is known from EP 0 507 707 A1. According thereto, an aerosol flow is superimposed with pressure fluctuations which are supposed to cause the aerosol particles/droplets in the main aerosol flow to pass through the ostia and enter the paranasal sinuses. In this way, even though the main aerosol flow does not directly flow through the paranasal sinuses, they can be reached and treated by a drug administered in aerosol form. As also with other types of aerosol therapy, it is attempted to deposit sufficient quantities of the drug at the desired points, for which in the case of the paranasal sinuses a sufficient quantity of the aerosol of the main aerosol flow must pass through the ostia and penetrate the paranasal sinuses.
DE 102 39 321 B3 provides an aerosol therapy device of the type described above, comprising a nebulizer having an aerosol generator to which compressed air is supplied for the generation of a main aerosol flow and having a connector for supplying pressure fluctuations which are superimposed on the main aerosol flow, and a nosepiece for supplying the aerosol to one of the two alae of the nose, which is connected to the nebulizer. A flow resistance device is furthermore provided, by means of which the flow resistance at the other of the two alae of the nose of the user is precisely defined. Owing to the flow resistance at the other nostril, the superimposed pressure fluctuations cause to a greater extent the aerosol of the main aerosol flow to also reach the paranasal sinuses and deposition of the aerosol there.
However, the supply of the flow of compressed gas and pressure fluctuations described in DE 102 39 321 B3 requires a specific design of the nebulizer, and thus not every nebulizer is suitable for this use.
Also of interest to the present invention is the treatment of diseases by delivering neurologic agents to the brain or central nervous system (CNS). Many drugs are not being effectively and efficiently delivered to the brain or CNS using conventional drug delivery system. Therapeutic treatment of various CNS disorders has been difficult to achieve because of the failures of drug delivery systems which target the CNS. Contributing factors to the difficulty include insufficient blood brain barrier penetration, rapid peripheral metabolism, poor intestinal absorption, inability to use synthetic precursors, and untoward side effects.
Particularly, the impermeability of the blood vessels of the brain referred to collectively as the blood-brain barrier (BBB) has posed difficulties. The blood vessels of the brain are unique when compared to the blood vessels found in the periphery of the body. Tight apposition of BBB endothelial cells (EC) to neural cells like astrocytes, pericytes and neurons induces phenotypic features that contribute to the observed impermeability. Tight junctions between ECs comprising the BBB limit paracellular transport, while the lack of pinocytotic vesicles and fenestrae limit non-specific transcellular transport. The tight junctures between endothelial cells in brain results in a very high trans-endothelial electric resistance of 1500-2000 W cm2 compared to 3-33 W cm2 of other tissues. These factors combine to restrict molecular flux from the blood to the brain to those molecules that are less than 500 Daltons and also lipophilic. Thus, using the large mass transfer surface area (over 21 m2 from 400 miles of capillaries in human brain) of the bloodstream as a delivery vehicle is largely infeasible except in those circumstances where a drug with the desired pharmacological properties fortuitously possesses the size and lipophilicity attributes allowing it to pass freely through the blood vessel. Because of such restrictions, it has been estimated that greater than 98% of all small molecule pharmaceuticals and nearly 100% of the emerging class of protein and gene therapeutics do not cross the BBB.
Intranasal drug delivery is of particular interest, as the brain and nose compartments are connected to each other via the olfactory route and via peripheral circulation. Studies have indicated ultrasound as a means to temporarily disrupt the BBB, thus allowing targeted drug delivery to the CNS. Since existing methods of delivery to the olfactory system have shown limited delivery, the present invention provides means to effectively deliver neurologic agents to the brain.
In view of the difficulties associated with current nebulization therapies in achieving aerosol deposition in the paranasal sinuses and CNS, the object of the present invention is to provide increased aerosol delivery and deposition in the paranasal sinuses and/or CNS via an aerosol therapy device wherein an aerosol is generated and supplied through to a patient's nasal cavities via a single pulsed main aerosol flow.